Nsaids-induced gastrointestinal mucosal disorder alleviator and manufacturing method thereof

ABSTRACT

[Problems] The object of the present invention is to provide a Medical Drugs which reduce damage of gastrointestinal mucosal induced by NSAIDs. 
     [Means for Solving Problems] 
     The Medical Drugs that comprises a mixture of NSAIDs and sugar that reduce damage of gastrointestinal mucosal induced by NSAIDs is already known. However the mixture is not enough to suppress damage of gastrointestinal mucosal. The inventors invented new molecular compounds with NSAIDs and trehalose. The new molecular compounds effectively reduce damage of gastrointestinal mucosal induced by NSAIDs.

TECHNICAL FIELD

The present invention relates to a Medical Drugs which reduce damage ofgastrointestinal mucosal induced by non-steroidal anti-inflammatoryDrugs, NSAIDs, and the method for manufacturing thereof.

BACKGROUND ART

NSAIDs, non-steroidal anti-inflammatory Drugs, are commonly used as apain killer, antipyretic, and anti-inflammatory Drugs. Even though theNSAIDs have a suitable effect, it has a drawback to induce damage ofgastrointestinal mucosal.

Japanese Patent Publication 2005-343886 disclose that damage ofgastrointestinal mucosal induced by Ibuprofen, which is categorized inNSAIDs, is reduced by mixing sugars (Patent document 1). However thealleviative effect caused by the mixture of Ibuprofen and sugars at adry sate is not sufficient.

Japanese Patent Publication 2005-139165 disclose that damage ofgastrointestinal mucosal induced by NSAIDs including Loxoprofen isreduced by mixing sugars (Patent document 2). However the alleviativeeffect caused by the mixture of NSAIDs and sugars at a dry state is notsufficient.

-   [Patent document 1] Japanese Patent Publication 2005-343886-   [Patent document 2] Japanese Patent Publication 2005-139165

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

The object of the present invention is to provide a Medical Drugs whichreduce damage of gastrointestinal mucosal induced by NSAIDs.

Means for Solving Problems

The present invention is basically based on the new substance that isIntermolecular compounds with NSAIDs and a disaccharide. As shown in thefollowing examples, the Intermolecular compounds, new compounds, haveextremely high effect to alleviate damage of gastrointestinal mucosalinduced by NSAIDs. The present invention is also related to a method formanufacturing the drug medicine which includes a step of manufacturingthe intermolecular compounds.

The first aspect of the invention relates to a Medical Drugs whichreduce damage of gastrointestinal mucosal induced by non-steroidalanti-inflammatory Drugs, NSAIDs, the Medical Drugs comprises anintermolecular compound of NSAIDs and a disaccharide; thereby theMedical Drugs has anti-inflammatory effect of the NSAIDs and can reducedamage induced by the NSAIDs. The Medical Drugs is manufactured by themethod of the invention. The method comprises a step of mixing adisaccharide and the NSAIDs so as to obtain a liquid mixture of thedisaccharide and the NSAIDs; and a step of drying the liquid mixture soas to obtain the Medical Drugs.

As shown in the following examples, the Intermolecular compounds, newcompounds, have extremely high effect to alleviate damage ofgastrointestinal mucosal induced by NSAIDs The example of a MedicalDrugs which reduce damage of gastrointestinal mucosal induced by NSAIDsis a Medical Drugs which reduce damage of gastric mucosal induced byNSAIDs.

As shown in the following examples, the drug medicine of the presentinvention which is manufactured by the above method interacts withmolecular. As shown in the following examples, the drug medicine(lyophilized agent) has reduce damage of gastrointestinal mucosalinduced by NSAID better than the mixture of NSAIDs and a disaccharide(mixture of powders). In other words, the drug medicine of the presentinvention, which is manufactured by the above method, has intermolecularcompound between NSAIDs and a disaccharide, thereby the intermolecularcompound effectively reduce damage of gastrointestinal mucosal inducedby NSAIDs.

As shown in the following working examples preferred NSAIDs are acidicNSAIDs. The example of the NSAIDs is one or more selected from the groupof “aspirin, sodium salicylate, salicylamide, sazapirin, diflunisal,ethenzamide, aluminum aspirin, 5-amino salicylic acidic, indomethacin,etodolac, sodium diclofenac, sulindac, sodium anfenac, proglumetacinmaleate, acemetacin, nabumeton, mofezolac, ibuprofen, naproxen,loxoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin, tiaprofenicacidic, pranoprofen, aluminoprophen, zaltoprofen, Mefenamic acidic,tolFenamic acidic, aluminum flufenamate, ketophenylbutazone, clofezone,bucolome, piroxicam, lornoxicam, tenoxicam, meloxicam, ampiroxicam,epirizole, tiaramide and elmofazon”. Within the above compounds, thepreferred NSAIDs are one or more of aspirin, indomethacin, sodiumdiclofenac, ibuprofen, piroxicam, loxoprofen and Mefenamic acidic. Thedrug medicine can effectively reduce damage of gastrointestinal mucosalinduced by NSAIDs by using the above NSAIDs.

A preferred working example of the first aspect of the invention is thatthe drug medicine comprises, as the disaccharide, one or more selectedfrom trehalose, maltose, lactose and sucrose. Trehalose is morepreferred as the disaccharide.

A preferred working example of the first aspect of the invention is thatthe form of the Medical Drugs is tablets, granules, or capsules. Thedisaccharides and NSAIDs are attached by means of molecular interactionsby dissolving disaccharides and NSAIDs jointly, drying the dissolveddisaccharides and NSAIDs and forming them into tablets, granules orcapsules. Thus such forms of Medical Drugs bring high reduction effectfor damage of gastrointestinal mucosal induced NSAIDs.

A preferred working example of the first aspect of the invention is thatthe NSAIDs is Indomethacin and the disaccharide is trehalose. Further,the DSC curve of the intermolecular compound obtained by the method ofdifferential scanning calorimetry, DSC, has a first peak and a secondpeak at 80 to 95 degrees Celsius and 260 to 270 degrees Celsius,respectively.

A preferred working example of the first aspect of the invention is thatthe NSAIDs is ibuprofen and the disaccharide is trehalose. Further theDSC curve of the intermolecular compound obtained by the method ofdifferential scanning calorimetry, DSC, has a third peak and a fourthpeak at 175 to 190 degrees Celsius and 130 to 145 degrees Celsius,respectively.

A preferred working example of the first aspect of the invention is thatthe NSAIDs is aspirin and the disaccharide is trehalose. Further the DSCcurve of the intermolecular compound obtained by the method ofdifferential scanning calorimetry, DSC, has a first peak and a secondpeak at 110 to 120 degrees Celsius and 135 to 145 degrees Celsius,respectively.

A preferred working example of the first aspect of the invention is thatthe NSAIDs is sodium diclofenac and the disaccharide is trehalose.Further the DSC curve of the intermolecular compound obtained by themethod of differential scanning calorimetry, DSC, has a first peak and asecond peak at 90 to 100 degrees Celsius and 130 to 145 degrees Celsius,respectively.

A preferred working example of the first aspect of the invention is thatthe NSAIDs is Mefenamic acidic and the disaccharide is trehalose.Further the DSC curve of the intermolecular compound obtained by themethod of differential scanning calorimetry, DSC, has a first peak and asecond peak at 225 to 235 degrees Celsius and 90 to 110 degrees Celsius,respectively. Still further the absolute values of the first peak andthe second peak are larger than absolute values of a peak at 225 to 235degrees Celsius and a peak at 90 to 110 degrees Celsius in a DSC curveof Mefenamic acidic obtained by the method of DSC, respectively.

A preferred working example of the first aspect of the invention is thatthe NSAIDs is piroxicam and the disaccharide is trehalose. Further theDSC curve of the intermolecular compound obtained by the method ofdifferential scanning calorimetry, DSC, has a first peak and a secondpeak at 90 to 105 degrees Celsius and 195 to 205 degrees Celsius,respectively. Still further, the absolute values of the first peak andthe second peak are smaller than absolute values of a peak at 90 to 105degrees Celsius and a peak at 195 to 205 degrees Celsius in a DSC curveof Mefenamic acidic obtained by the method of DSC, respectively.

The second aspect of the invention relates to above described MedicalDrugs in which the Medical Drugs is a Medical Drugs of alleviatingdamage of gastric mucosal. The Medical Drugs is manufactured by themethod of the invention. The method comprises a step of mixing adisaccharide and the NSAIDs so as to obtain a liquid mixture of thedisaccharide and the NSAIDs; and a step of drying the liquid mixture soas to obtain the Medical Drugs. As shown by the following examples, bymaking a drug medicine through the above method, it is possible tomanufacture a drug medicine which can effectively strengthen thetechnical effect of the disaccharide that reduce damage ofgastrointestinal mucosal induced by NSAIDs.

As shown in the following working examples preferred NSAIDs are acidicNSAIDs. The example of the NSAIDs is one or more selected from the groupof “aspirin, sodium salicylate, salicylamide, sazapirin, diflunisal,ethenzamide, aluminum aspirin, 5-amino salicylic acidic, indomethacin,etodolac, sodium diclofenac, sulindac, sodium anfenac, proglumetacinmaleate, acemetacin, nabumeton, mofezolac, ibuprofen, naproxen,loxoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin, tiaprofenicacidic, pranoprofen, aluminoprophen, zaltoprofen, Mefenamic acidic,tolFenamic acidic, aluminum flufenamate, ketophenylbutazone, clofezone,bucolome, piroxicam, lornoxicam, tenoxicam, meloxicam, ampiroxicam,epirizole, tiaramide and elmofazon”. Within the above compounds, thepreferred NSAIDs are one or more of aspirin, indomethacin, sodiumdiclofenac, ibuprofen, piroxicam, loxoprofen and Mefenamic acidic. Thedrug medicine can effectively reduce damage of gastrointestinal mucosalinduced by NSAIDs by using the above NSAIDs.

Effect of the Invention

The present invention can provide a Medical Drugs which reduce damage ofgastrointestinal mucosal induced by NSAIDs without decreasing thetechnical effect caused by NSAIDs.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph, which is a substitute of a drawing, which shows ulcerindex (mm²) when test substances are administered.

FIG. 2 is a graph, which is a substitute of a drawing, which shows a ratulcer index (mm²) when indomethacin alone, a mixture of indomethacin andtrehalose and lyophilized indomethacin and trehalose are administered.

FIG. 3 is a graph, which is a substitute of a drawing, which shows a ratulcer index (mm²) when aspirin alone, a mixture of aspirin and trehaloseand lyophilized aspirin and trehalose are administered.

FIG. 4 is a graph, which is a substitute of a drawing, which shows a ratulcer index (mm²) when diclofenac alone, a mixture of diclofenac andtrehalose and lyophilized diclofenac and trehalose are administered.

FIG. 5 is a graph, which is a substitute of a drawing, which shows aneffect for gastric mucosal damages with lyophilized state and mixedstate. FIG. 5A is a graph, which is a substitute of a drawing, whichshows cell viability rate. FIG. 5B is a graph, which is a substitute ofa drawing, which shows cell lethality rate.

FIG. 6 is a graph, which is a substitute of a drawing, which shows theresult of DSC of torehalose alone, indomethacin alone, a mixture ofindomethacin and trehalose and lyophilized indomethacin and torehalose.

FIG. 7 is a graph, which is a substitute of a drawing, which shows theresult of DSC of torehalose alone, ibuprofen alone, a mixture ofibuprofen and trehalose and lyophilized ibuprofen and torehalose.

FIG. 8 is a graph, which is a substitute of a drawing, which shows theresult of DSC of torehalose alone, aspirin alone, a mixture of aspirinand trehalose and lyophilized aspirin and torehalose.

FIG. 9 is a graph, which is a substitute of a drawing, which shows theresult of DSC of torehalose alone, diclofenac alone, a mixture ofdiclofenac and trehalose and lyophilized diclofenac and torehalose.

FIG. 10 is a graph, which is a substitute of a drawing, which shows theresult of DSC of torehalose alone, piroxicam alone, a mixture ofpiroxicam and trehalose and lyophilized piroxicam and torehalose.

FIG. 11 is a graph, which is a substitute of a drawing, which shows theresult of DSC of torehalose alone, Mefenamic acidic alone, a mixture ofMefenamic acidic and trehalose and lyophilized Mefenamic acidic andtorehalose.

FIG. 12 is a graph, which is a substitute of a drawing, which shows theresult of measurement of ulcer area when each of maltose, sucrose, andlactose were lyophilized with aspirin to conform a molecular compound.

FIG. 13 is a graph, which is a substitute of a drawing, which shows theresult of measurement of ulcer area when each of maltose and lactosewere lyophilized with diclofenac to conform a molecular compound.

BEST MODE FOR CARRYING OUT THE INVENTION

The first aspect of the invention relates to a Medical Drugs whichreduce damage of gastrointestinal mucosal induced by non-steroidalanti-inflammatory Drugs, NSAIDs, the Medical Drugs comprises anintermolecular compound of NSAIDs and a disaccharide; thereby theMedical Drugs has anti-inflammatory effect of the NSAIDs and canalleviate damage induced by the NSAIDs. The Medical Drugs ismanufactured by the method of the invention. The method comprises a stepof mixing a disaccharide and NSAIDs so as to obtain a liquid mixture ofthe disaccharide and the NSAIDs; and a step of drying the liquid mixtureso as to obtain the Medical Drugs. The liquid mixture comprisesdissolved disaccharide and dissolved NSAIDs. A Medical Drugs whichreduce damage of gastrointestinal mucosal induced by NSAIDs is a drugmedicine that can alleviate damage of gastrointestinal mucosal inducedby NSAIDs, which keeps the anti-inflammatory effect caused by NSAIDs. Itis preferred for the Medical Drugs of the invention to comprisedisaccharide and NSAIDs that have molecular interactions between them.It is preferred for the Medical Drugs of the invention to comprise aneffective amount of disaccharide to alleviate damage of gastrointestinalmucosal induced by NSAIDs. Namely, disaccharide and NSAIDs that havemolecular interactions between them are main ingredients for alleviatingdamage of gastrointestinal mucosal induced by NSAIDs.

In this specification, the term damage of gastrointestinal mucosalinduced by NSAIDs includes not only pathological changes of gastricmucosa (e.g. erosion, ulcer, and edema) induced by NSAIDs but alsodisorders of duodenum which is close part of stomach and disorders ofsmall intestine and large intestine. In this specification, the termGastrointestinal Tract includes stomach, duodenum, small intestine andlarge intestine. NSAIDs may bring intestinal perforation at smallintestine. The Medical Drugs which reduce damage of gastrointestinalmucosal induced by NSAIDs is effective for an intestinal perforation atsmall intestine caused by NSAIDs. As shown by the examples, the presentinvention is most effective for Gastric mucosal disorders. Namely, themost effective working example of the Medical Drugs which reduce damageof gastrointestinal mucosal induced by NSAIDs of the present inventionis the Medical Drugs which reduce damage of gastric mucosal induced byNSAIDs.

The examples of disaccharide are maltose, sucrose, cellobiose, lactose,and trehalose. Within these disaccharides, the preferred disaccharidesare maltose, sucrose, lactose, and trehalose, and most preferabledisaccharide is trehalose.

Trehalose is one of disaccharides in which two D-glucoses are connected.Trehalose has three isomers, which are different in their connectingstyle, α, α body (α-D-glucopyranosyl α-D-glucopyranoside), α, β body(β-D-glucopyranosyl α-D-glucopyranoside)) and β, β body(β-D-glucopyranoyl β-D-glucopyranoside)). As for the present invention,if the Medical Drugs comprises effective amount of one or more of theseisomers in total, it is possible to use any isomers produced by anyproduction method, with any purity and with any states.

NSAIDs, non-steroidal anti-inflammatory Drugs, are drug medicines ofnon-steroidal anti-inflammatory drugs. The drug medicine of the presentinvention may comprise each of acidic NSAIDs and base NSAIDs. PreferredNSAIDs of the invention is acidic NSAIDs. Further preferred NSAIDs ofthe invention is Carboxylic acidic NSAIDs. The drug medicine of theinvention may comprise one or more kinds of NSAIDs. When the drugmedicine comprises 2 or more kinds of NSAIDs, the drug medicine maycomprise NSAIDs in the same category (for example, two kinds ofsalicylic acidic NSAIDs) or NSAIDs in the different categories (forexample, salicylic acidic NSAID and Aryl acetic acidic NSAID). TheseNSAIDs may be manufactured using well known methods or it is possible touse commercially obtainable NSAIDs.

NSAIDs are categorized in salicylic acidic NSAIDs, aryl acetic acidicNSAIDs, propionic acidic NSAIDs, Fenamic acidic NSAIDs, enol acidicNSAIDs, and basic NSAIDs. The examples of salicylic acidic NSAIDs areaspirin, sodium salicylate, salicylamide, sazapirin, diflunisal,ethenzamide, aluminum aspirin, and 5-amino salicylic acidic.

The examples of aryl acetic acidic NSAIDs are indomethacin, etodolac,sodium diclofenac, sulindac, sodium anfenac, proglumetacin maleate,acemetacin, nabumeton, and mofezolac.

The examples of propionic acidic NSAIDs are ibuprofen, naproxen,loxoprofen, flurbiprofen, flurbiprofen axetil, oxaprozin, tiaprofenicacidic, pranoprofen, aluminoprophen and zaltoprofen.

The examples of Fenamic acid are Mefenamic acidic, tolfenamic acidic,and aluminum flufenamate.

The examples of enol acidic NSAIDs are Pyrazolone NSAIDs, PyrimidineNSAIDs and oxycum NSAIDs. The examples of Pyrazolone NSAIDs areketophenylbutazone and clofezone. The example of Pyrimidine NSAIDs isbucolome. The examples of oxycum NSAIDs are piroxicam, lornoxicam,tenoxicam, meloxicam, and ampiroxicam.

The examples of basic NSAIDs are epirizole, tiaramide and elmofazon.

It is thought that the drug medicine of the invention has intermolecularbonding by means of molecular interactions. The term intermolecularbonding means that two or more molecules connect each other. Theexamples of such intermolecular bonding are ionic bonding, complexbonding, hydrophobic bonding, hydrogen bonding, and van der Waalsbonding. The drug medicine of the invention, which has such a bonding,can be manufactured by means of the method explained below. It ispossible to investigate that the molecular interaction of NSAIDs anddisaccharide that are included in the manufactured drug medicine bymeans of conventional analysis methods. The examples of the analysismethods are DSC (Differential Scanning Calorimetry), FTIR (FourierTransform Infrared Spectroscopy), XPS (X-ray photoelectron spectroscopy)and NMR (nuclear magnetic resonance). The skilled person would be ableto analyze the molecular interaction by means of the conventionalmethod.

It is possible for the drug medicine of the invention to comprise apharmaceutically acceptable carrier or a pharmaceutically acceptablemedium. The examples of the pharmaceutically acceptable carrier and apharmaceutically acceptable medium are the pharmaceutically acceptablesubstances including an anti oxidant and a retainer. It is possible touse polymers like Polyethylene glycol (PEG), and Conjugated compoundssuch as cyclodextrin. The followings are the examples but the presentinvention is not limited to such examples. The examples of thestabilizer are albumin, gelatin, sorbitol, mannitol, lactose, sucrose,maltose, and glucose. The examples of the anti-oxidant are sodiumsulfite, ascorbic acidic, tocopherol, cysteine hydrochloride,thioglycolic acidic, and catechol. The examples of the retainer arephenol, thimerosal, and benzalkonium chloride.

The Medical Drugs of the invention is manufactured by the method of theinvention. The method comprises a step of mixing a disaccharide andNSAIDs so as to obtain a liquid mixture of the disaccharide and theNSAIDs; and a step of drying the liquid mixture so as to obtain theMedical Drugs. The liquid mixture comprises dissolved disaccharide anddissolved NSAIDs. The examples of the step of drying are a step oflyophilize, a step of Granulating and Spray Drying, a step of spraydrying and a step of Crushing after drying for granulation.Conventionally, the skilled person would mix powdered NSAIDs andpowdered disaccharides to manufacture powdered drug medicine. Further,to manufacture a liquid drug medicine, the skilled person would mixNSAIDs solution and disaccharide solution, would pour powdered NSAIDsand powdered disaccharides separately into a liquid and would stir thesolution so as to dissolve the powders, or would pour the mixture ofpowders that includes powdered NSAIDs and powdered disaccharides into aliquid and would stir the solution so as to dissolve the powders.However, as is shown by the following examples, the mixed solution ofNSAIDs solution and disaccharide solution has not sufficient effect toalleviate damage of gastrointestinal mucosal induced by NSAID. Thereason of the fact is thought that the disaccharide and NSAIDs in liquiddrug medicine do not form intermolecular connections enough. The presentinvention intentionally makes NSAIDs and disaccharide to be dissolved toobtain a liquid mixture so as to bring interactions and then the presentinvention makes the liquid mixture to be dried so as to obtain a MedicalDrugs that has enough activity to reduce damage of gastrointestinalmucosal induced by NSAID. The drug medicine manufactured by the methodhas molecular interactions as explained below. Namely, the drug medicinemanufactured by the method comprises molecular interactions betweendisaccharide and NSAIDs. The drug medicine of the invention thereforehas NSAIDs molecular dispersed into disaccharide molecules with keepingmolecular interactions of NSAIDs and thus it can alleviate damage ofgastrointestinal mucosal induced by NSAID effectively.

[Step of Mixing]

The step of mixing is a step for mixing a disaccharide and NSAIDs so asto obtain a liquid mixture of the disaccharide and the NSAIDs. Theliquid mixture comprises dissolved disaccharide and dissolved NSAIDs.The examples of solvates for dissolving disaccharide and NSAIDs jointlyare already known solutions that are used for manufacturing drugmedicine that includes water, distilled water, de-ionized water, Milli Qwater, and saline. It is possible to obtain a liquid mixture by mixingNSAIDs solution and disaccharide solution. It is possible to obtain aliquid mixture by the method that includes dissolving one of powderedNSAIDs and powdered disaccharides to obtain a liquid solution of oneingredient and then dissolving other ingredient into the solution.Further it is possible to obtain a liquid mixture by mixing anddissolving powdered NSAIDs and powdered disaccharides into a liquid.Further it is possible to dissolve NSAIDs into a solvate such as ethanolbecause NSAIDs has less solubility and make such NSAIDs to be dissolvedand then disaccharides are dissolved into the solution to obtain themixed solution. The example of the weight rate of NSAIDs anddisaccharides in the mixed solution is 1×10²:1˜1:1×10², preferably is1×10:1˜1:5×10 and more preferably is 1:1˜1:1×30. The example of theconcentration of disaccharide in the mixed solution in manufacturing theMedical Drugs of the invention is 1×10⁻²˜5×10 wt %, preferably is1×10⁰˜4.5×10 wt % and more preferably is 1×10˜4×10 wt %.

[Step of Lyophilization]

The step of lyophilization is a step of sublimating water from thefreeze sample under decompression circumstance. The step oflyophilization may have following steps.

(1) Cooling the sample (mixed solution) by keeping it for 2 to 3 hoursunder 4 degrees C., at Ordinary pressure (Cooling step);(2) Freezing the sample by keeping it for 12 to 15 hours under −50degrees C. at Ordinary pressure (Freezing step);(3) Crystallizing the sample by keeping it for 4 to 6 hours under −20degrees C. at Ordinary pressure (Crystallizing step);(4) Refreezing the sample by keeping it for 14 to 16 hours under −50degrees C. at Ordinary pressure (Refreezing step);(5) Drying the sample by keeping it for 24 to 26 hours under −13 degreesC. at 10 to 20 kPa (under high vacuum) (the first drying step);(6) Drying the sample by keeping it for 10 to 121 hours under 24 degreesC. at 10 to 20 kPa (under high vacuum) (the second drying step); and(7) Keeping the sample under 24 degrees C. at Ordinary pressure. Themethod of lyophilization of the above freezes the sample at lowtemperature and sublimates water (ice) under high vacuum. Thelyophilized compound of the invention may be manufactured in accordancewith the above described protocol. However, the method of lyophilizationis not limited to the above protocol and the skilled person may alterthe parameters that include temperatures, pressures, and duration timesof each of steps.

[Step of Granulating and Spray Drying]

The method of Granulating and Spray Drying is a method for obtain driedgranules by contacting hot wind to the samples that include moiety withmoving the samples. The step of Granulating and Spray Drying is attainedby means of already known Granulating and Spray Drying apparatus.

The drug medicine of the invention may be manufactured in accordancewith the following steps.

(1) pre drying the sample by attaching hot wind of 50 to 100 degrees C.with 1 to 2 m/s speed for 10 to 30 minutes to the sample with stirringthe sample (mixed solution) (pre drying step);(2) granulating the sample by attaching hot wind of 20 to 50 degrees C.with 2 to 3 m/s speed for 30 minutes to 1 hour to the sample(granulating step);(3) drying the sample by attaching hot wind of 50 to 100 degrees C. with1 to 2 m/s speed for 30 minutes to 2 hours to the sample (drying step);and(4) cooling the sample by attaching cool wind of 5 to 20 degrees C. with1 to 2 m/s speed for 10 minutes to 60 minutes to the sample (coolingstep).

The method of Granulating and Spray Drying obtain granules by attachinghot wind to the sample so as to dry the sample with the sample floatingin the air. The drug medicine of the invention may be manufactured inaccordance with the above described protocol. However, the method ofGranulating and Spray Drying is not limited to the above protocol andthe skilled person may alter the parameters that include temperatures,pressures, and duration times of each of steps.

The examples of the form of the Medical Drugs of the invention when theMedical Drugs is manufactured by means of the method of Granulating andSpray Drying are tablets, granules, or capsules. It is possible tomanufacture tablets, granules, or capsules by compacting Medical Drugsusing conventional compacting method, in which the Medical Drugs aremanufactured by wet granulating method. It is possible to obtain capsuledrug medicine by filling tablets or granules into the capsule. Thevolume of the each of the drug medicine is not limited but it ispossible to adjust the volume based on the amount of disaccharides andNSAIDs. The disaccharides and NSAIDs are attached by means of molecularinteractions by dissolving disaccharides and NSAIDs jointly, drying thedissolved disaccharides and NSAIDs and forming them into tablets,granules or capsules. Such forms of Medical Drugs bring high alleviativeeffect for damage of gastrointestinal mucosal induced NSAIDs. Thus theabove described forms of the Medical Drugs are preferred.

[Step of Spray Drying]

The step of spray drying (Step of spray drying) is a step of dryingobject quickly by spraying liquid samples with heated wind though narrownozzle such that the samples become minute drops in the chamber. It ispossible to manufacture the spray dried object by means of aconventional spray dryer. It is possible to manufacture the MedicalDrugs of the invention using the following steps.

(1) spraying samples (mixed solution) though nozzle with 0.5 to 1 mmaperture with heated wind of 100 to 300 degrees C. into the chamber,with air pressure of 0.5 to 2.5 kg/m² and flow speed of 25 to 50 l/min(spray step);(2) drying sprayed samples by contacting heated wind of 100 to 300degrees C. with flow speed of 0.5 to 1 m/s for 30 seconds to 5 minutes(drying step).

As described the above the method of spray drying is the method fordrying and granulating samples by contacting heated wind to the minutedrops that are made by spraying the sample into high temperaturechamber. It is possible to manufacture the Medical Drugs of theinvention by means of the above method. However the invention is notlimited to the Medical Drugs manufactured the above method. It ispossible for the skilled person to adjust the parameters that includetemperature and duration time for each step.

[Step of Crushing after Drying for Granulation]

The step of crushing after drying for granulation is a step formanufacturing granules by crushing dried samples that contained moiety.It is possible to manufacture the Medical Drugs of the invention isbased on the following steps.

(1) stirring samples (mixed solution) for 1 to 5 hours with attachinghot wind of 50 to 80 degrees C. and stirring speed of 10 to 100 roundper minute (drying step);(2) cooling samples by contacting cold wind of 5 to 15 degrees C. withthe dried samples (Cooling step);(3) crushing the cooled samples by means of a crasher (crushing step);and(4) sieving the crashed samples by means of a sieving apparatus withpredetermined size of sieves (sieving step).

As described the above the method of Crushing after drying forgranulation is a method for manufacturing a powders with predeterminedsize by crashing lump of samples. It is possible to manufacture theMedical Drugs of the invention by means of the above method. However theinvention is not limited to the Medical Drugs manufactured the abovemethod. It is possible for the skilled person to adjust the parametersthat include temperature and duration time for each step.

It is possible to manufacture the molecular compound of disaccharide andNSAIDs by melting and mixing disaccharide and NSAIDs under an anaerobiccondition and at the temperature higher than the melting point ofdisaccharide and NSAIDs. However the Medical Drugs manufactured by theabove methods were superior to the Medical Drugs manufactured by themethod in the effect of alleviating damage of gastrointestinal mucosalinduced by NSAID effectively.

The apparatus for dissolving and mixing is already known. It is possibleto use such conventional apparatus to execute the dissolving and mixingstep. The example of apparatus for executing the dissolving and mixingstep is a satirizing apparatus. It is possible to obtain crystal ofmolecular compound by stirring mixed solution of disaccharide and NSAIDsat the temperature that is higher than the melting point of disaccharideand NSAIDs and by executing static crystallization after the stirringfor predetermined time. It is possible to obtain molecular compound withhigh purity by repeating the processes of melting, stirring andexecuting static crystallization.

The melting and mixing step is executed under an anaerobic condition.More specifically, the melting and mixing step is executed under theexistence of nitrogen gas or inert gas. The examples of the inert gasare noble gases and the examples of the novel gases are helium, neon,argon, and krypton. Within the noble gasses, argon is most preferred.

The melting and mixing step is executed under atmospheric pressure,reduced pressure and high pressure. It is possible to use conventionalcatalyst at the melting and mixing step.

It is possible to obtain the molecular compound of disaccharide andNSAIDs by contact melting of crystals of disaccharide and NSAIDs as wellas the method as described above. However the Medical Drugs manufacturedby the above methods were superior to the Medical Drugs manufactured bythe method in the effect of alleviating damage of gastrointestinalmucosal induced by NSAID effectively.

It is possible to execute the contact melting of disaccharide and NSAIDsby means of a bicrystal furnace. The bicrystal furnace is an apparatusthat can control the boundary at which seed crystals contact (grainboundary) and grow the seed crystals by melting contacted part ofingredients crystals and moving the cast. More specifically, the methodof contact melting is the method that comprises crashing crystals ofdisaccharide and NSAIDs continuously for a long period, locallydissolving contacted points of crystals and growing the molecularcompound of disaccharide and NSAIDs.

The Medical Drugs of the invention manufactured as described the abovehas effects of anti-inflammatory, analgesic, and antipyretic of NSAIDs.The Medical Drugs of the invention which comprises disaccharide andNSAIDs can alleviate damage of gastrointestinal mucosal induced by NSAIDand thus it is possible to be used for the patients whom NSAIDs areeffective to cure or prevent diseases to take an effective amount of theMedical Drugs of the invention. In other words, the present inventionprovides a method for treatment or prevent method which include a stepof giving a Medical Drugs which reduce damage of gastrointestinalmucosal induced by NSAIDs to an object. The object may be a human. Thepreferred example of the Medical Drugs which reduce damage ofgastrointestinal mucosal induced by NSAIDs that comprises disaccharideand NSAIDs with molecular interactions are the Medical Drugs which ismanufactured by a step of lyophilization or a step of wet granulating.

NSAIDs usually have stimulated taste such as sour taste and bitter tasteand thus the taste of NSAIDs is not suitable for oral doses. However theMedical Drugs of the invention comprises disaccharide as well as NSAIDsin which disaccharide and NSAIDs have molecular interactions.

The disaccharide softens the taste of NSAIDs. Thus it is possible toimprove the taste of tablets that comprise NSAIDs and, especially thetaste of granules. The Medical Drugs of tablet form, especially ofgranules, is easy to take. Further anti-oxidant effect of disaccharidestrengthens the chemical stability of NSAIDs.

The Medical Drugs manufactured by the above method is mainly used fororal doses. However it is possible to use the Medical Drugs of theinvention to non oral doses. When the Medical Drugs of the invention isused as an oral dose, the patient shall take the Medical Drugs togetherwith a pharmaceutically acceptable solution such as water. The exampleof non oral dose is syringe. When the Medical Drugs of the invention isgiven by means of syringe, the Medical Drugs should be dissolve into apredetermined pharmaceutically acceptable solvent such that the solutioncontains predetermined concentrate. The examples of the pharmaceuticallyacceptable solvent are water for injection, saline solution, and glucosesolution.

The amount of dose varies in accordance with the kind of patient, theage of patient and symptoms. In general, the daily dose is from 10 mg to1000 mg, preferably from 100 mg to 500 mg, of NSAIDs as a part of anactive ingredient. It is possible to give the Medical Drugs of theinvention twice to five times a day. By giving the medical Drugseparately to several times it is possible to escape drastic change ofconcentrate of the Medical Drugs in blood and it is possible to preventside effect and reduce load to the patient.

A preferred working example of the invention is to provide a use ofdisaccharide and NSAIDs in manufacturing a Medical Drugs which reducedamage of gastrointestinal mucosal induced by NSAIDs. Further thepresent invention provide a use of disaccharide and NSAIDs that haveintermolecular bonding for manufacturing a Medical Drugs which reducedamage of gastrointestinal mucosal induced by NSAID. A preferred exampleof the disaccharide and NSAIDs that have intermolecular bonding arethose manufactured by the methods of lyophilization or wet granules. Itis possible to use the above explained one or more kinds of NSAIDs.

We explain the working examples of the invention. However the inventionis not limited to the following examples.

Working Example 1

The reduce effect of trehalose for the damage of gastrointestinalmucosal induced by NSAIDs

1. Test Samples

In this example, aspirin, indomethacin, ibuprofen, and sodium diclofenacwere used as NSAIDs. We bought aspirin, indomethacin and ibuprofen fromWako Pure Chemical Industries and bought sodium diclofenac from CaymanInc. We used trehalose manufactured by Hayashibara and used Sodiumcarboxy-methyl cellulose manufactured by Dai-ichi Kogyo Seiyaku Co.,Ltd.

2. Preparation of Lyophilized Trehalose.NSAIDS

We prepared 30% (w/v) trehalose solution using purified water (Milli Qgrade (milli Q water)). Suitable amount of NSAIDs were dissolved in99.5% ethyl alcohol and mixed with trehalose solution at suitable ratio.After enough stirred, the mixed solutions were dried for more than 48hours by means of a lyophilizing apparatus (Tokyo Rika Co., EYELA,lyophilizing apparatus, FDU-1100).

Specifically the preparation was executed by the following steps.

(1) Trehalose was dissolved in milli Q water so as to obtain 30% (w/v)trehalose solution(2) 1.0 g of each of NSAIDs was dissolved in 2.0 mL ethyl alcohol.(3) Suitable amount of trehalose solutions were added to the ethylalcohol solutions in which each of NSAIDs was dissolved. Please notethat indomethacin and ibuprofen solution brings precipitation if all ofthe trehalose solution required were to be added. Thus as for theindomethacin and ibuprofen solution, maximum amount of trehalosesolutions which were not bring precipitation were added and then themixed solutions were stirred for about 10 to 20 minutes.(4) Milli Q water was added so that the final concentrate of ethylalcohol to be less than 10%, preferably less than 5%. As for aspirin andsodium diclofenac, it was not found precipitation. Thus each of thesolutions of and sodium diclofenac was stirred for about 10 to 20minutes.(5) The mixed solutions were dried for more than 48 hours by means of alyophilizing apparatus (Tokyo Rika Co., EYELA, lyophilizing apparatus,FDU-1100).

Each of the test substances were adjusted by suspending or dissolvingthem into 0.5% CMC.Na solution. Each of 9 mL of Liquid doses was givenper 1 kg weight by oral dose. 0.5% CMC.Na solutions were given tocontrol group.

3. Animal

We bought Winster male rats (Japan SLC) that were 8 weeks old. We breedthese rats keeping 20 to 26 degrees C., humidity of 30 to 70%, housing 2to 3 rats in a rat breeding gage (mouse and rat breeding CE-2), givingenough amount of filtered tap water. After breeding 7 days, 5 to 10 ratsper group were picked to execute the example. The rats were fasting for24 hours without giving no food and then the rats were fed no food andno water for 1 hour just before the examination.

4. Method

From 11 am on the previous day of the examination date, the rats werekept fasting and test substances were fed though mouse. After 5 hourspassed, these rats were killed by carbon dioxide gas and stomachs werepicked up. The duodenums were tagged. 6 mL of neutral formalin waspoured from the esophagi so as to fix the stomachs for 30 minutes. Thestomachs were cut along with the greater curvature. The cut stomachswere gently washed by saline, the presence of blood spot were observedby a stereoscopic microscope. The area of blood spots was measured by0.5 mm×0.5 mm unit as an index of ulcer and the sum of each animal wascalculated. The rate of suppressed ulcer was calculated, using the ulcerindex for the group in which each of test sample was given and the groupin which trehalose was also given, in accordance with the followingequation.

Rate of suppressed ulcer(%)=[1−A/B]×100

-   -   A: Ulcer index for the group in which NSAID was given alone    -   B: Ulcer index for the group in which NSAID and trehalose was        given

5. Result

Obtained rate of suppressed ulcer for the group in which trehalose wasalso given was shown in table 1 and FIG. 1.

TABLE 1 Rate of suppressed Test substances(mg/kg) ulcer (%)Indomethacin(30) + Trehalose(800) 38.3 Ibuprofen(400) + Trehalose(800)64.5 Aspirin(200) + Trehalose(800) 71.6 Diclofenac(40) + Trehalose(800)61.6

FIG. 1 is a graph, which is a substitute of a drawing, which shows ulcerindex (mm2) when test substances are administered. The horizontal axisof FIG. 1 indicates that the tested substances that were administered.The vertical axis of FIG. 1 indicates the area of ulcer. The resultshows that, for all of NSAIDs, when lyophilized NSAIDs as well astrehalose were administered have a tendency to suppress the generationof ulcer compared to NSAIDs alone were administered.

The stomach ulcer model induced by indomethacin was examined. Whenindomethacin alone (30 mg/kg) was administered ulcer of 4.83±0.90(average of 10 cases±standard deviation) mm² was observed. Whenlyophilized indomethacin and trehalose (30 mg/kg of indomethacin and 800mg/kg of trehalose) was administered 2.98±0.90 (average of 10cases±standard deviation) mm² was observed. Thus the rate of suppressedulcer caused by lyophilizing was 38.8%.

The stomach ulcer model induced by ibuprofen was examined. Whenibuprofen alone (400 mg/kg) was administered ulcer of 5.35±1.86 (averageof 5 cases±standard deviation) mm² was observed. When lyophilizedibuprofen and trehalose (400 mg/kg of ibuprofen and 800 mg/kg oftrehalose) was administered 1.90±0.69 (average of 5 cases±standarddeviation) mm² was observed. Thus the rate of suppressed ulcer caused bylyophilizing was 64.5%.

The stomach ulcer model induced by aspirin was examined. When aspirinalone (200 mg/kg) was administered ulcer of 10.40±2.80 (average of 5cases±standard deviation) mm² was observed. When lyophilized aspirin andtrehalose (200 mg/kg of aspirin and 800 mg/kg of trehalose) wasadministered 3.00±1.20 (average of 5 cases±standard deviation) mm² wasobserved. Thus the rate of suppressed ulcer caused by lyophilizing was71.2%.

The stomach ulcer model induced by diclofenac was examined. Whendiclofenac alone (40 mg/kg) was administered ulcer of 4.30±0.71 (averageof 10 cases±standard deviation) mm² was observed. When lyophilizeddiclofenac and trehalose (40 mg/kg of diclofenac and 800 mg/kg oftrehalose) was administered 1.65±0.43 (average of 10 cases±standarddeviation) mm² was observed. Thus the rate of suppressed ulcer caused bylyophilizing was 61.6%.

The working example 1 shows that by using lyophilized NSAIDs andtrehalose, it is possible to suppress ulcer.

Working Example 2 Suppression of Gastric Mucosal Disorder by MolecularInteractions Between Trehalose and NSAIDs 1 1. Test Substances

In this example, indomethacin, aspirin and sodium diclofenac were usedas NSAIDs. We bought indomethacin from Wako Pure Chemical Industries andbought sodium diclofenac from Cayman Inc. We used trehalose manufacturedby Hayashibara and used Sodium carboxy methyl cellulose manufactured byDai-ichi Kogyo Seiyaku Co., Ltd.

2. Preparation of Lyophilized Trehalose.NSAIDS

We prepared 30% (w/v) trehalose solution using purified water (Milli Qgrade (milli Q water)). Suitable amount of NSAIDs were dissolved in99.5% ethyl alcohol and mixed with trehalose solution at suitable ratio.After enough stirred, the mixed solutions were dried for more than 48hours by means of a lyophilizing apparatus (Tokyo Rika Co., EYELA,lyophilizing apparatus, FDU-1100).

3. Preparation of Liquid Dose

The liquid doses were prepared on the date when the examination wasexecuted. Weighted NSAIDs were suspended or dissolved into 0.5% CMC.Nasolution to prepare doses of administrating NSAIDs only. Suspension ofNSAIDs and solution of trehalose were prepared. Then the same amount ofthe suspension and solution were mixed to prepare the dosed of mixtureof trehalose and NSAIDs just before administrating them. Predeterminedamount of lyophilized compounds that contains lyophilized trehalose andNSAIDs with predetermined rate were weighted and each of them was mixedwith 0.5% CMC.Na solution to prepare doses of lyophilized trehalose andNSAIDs. For each groups the amount of dose was 8 mL per kg or rat.

4. Animal

We bought Winster male rats (Japan SLC) that were 8 weeks old. We breedthese rats keeping 20 to 26 degrees C., humidity of 30 to 70%, housing 2to 3 rats in a rat breeding gage (mouse and rat breeding CE-2), givingenough amount of filtered tap water. After breeding 7 days, 5 to 10 ratsper group were picked to execute the example. The rats were fasting for24 hours without giving no food and then the rats were fed no food andno water for 1 hour just before the examination.

5. Method of Producing Gastric Mucosal Disorder and Evaluation

From 11 am on the previous day of the examination date, the rats werekept fasting and test substances were fed though mouse. After 5 hourspassed, these rats were killed by carbon dioxide gas and stomachs werepicked up. The duodenums were tagged. 6 mL of neutral formalin werepoured from the esophagi so as to fix the stomachs for 30 minutes. Thestomachs were cut along with the greater curvature. The cut stomachswere gently washed by saline, the presence of blood spot were observedby a stereoscopic microscope.

The area of blood spots was measured by 0.5 mm×0.5 mm unit as an indexof ulcer and the sum of each animals was calculated. The rate ofsuppressed ulcer was calculated, using the ulcer index for the group inwhich each of test samples were given and the group in which trehalosewas also given, in accordance with the following equation.

Rate of suppressed ulcer(%)=[1−A/B]×100

-   -   A: Ulcer index for the group in which NSAID was given alone    -   B: Ulcer index for the group in which NSAID and trehalose was        given

6. Result

Measured area of ulcer for the groups in which indomethacin alone wasgiven, mixed indomethacin and trehalose, and lyophilized indomethacinand trehalose were given was shown in table 2.

TABLE 2 Ulcer index (mm², average ± Test substances(mg/kg) standarddeviation) Indomethacin alone 4.83 ± 0.90 Indomethacin + Trehalose(mixed) 4.15 ± 0.86 Indomethacin + Trehalose (lyophilized) 2.98 ± 0.54

Measured area of ulcer for the groups in which aspirin alone was given,mixed aspirin and trehalose, and lyophilized aspirin and trehalose weregiven was shown in table 3.

TABLE 3 Ulcer index (mm², average ± Test substances(mg/kg) standarddeviation) Aspirin alone 10.40 ± 2.73  Aspirin + Trehalose (mixed) 9.25± 3.45 Aspirin + Trehalose (lyophilized) 2.95 ± 1.14

Measured area of ulcer for the groups in which diclofenac alone wasgiven, mixed diclofenac and trehalose, and lyophilized diclofenac andtrehalose were given was shown in table 4

TABLE 4 Ulcer index (mm², average ± Test substances(mg/kg) standarddeviation) Diclofenac alone 4.30 ± 0.71 Diclofenac + Trehalose (mixed)4.20 ± 1.11 Diclofenac + Trehalose (lyophilized) 1.65 ± 0.43

The results of ulcer index (mm²) when indomethacin, aspirin, ordiclofenac was administered are shown in FIG. 2, FIG. 3 and FIG. 4.

FIG. 2 is a graph, which is a substitute of a drawing, which shows a ratulcer index (mm²) when indomethacin alone, a mixture of indomethacin andtrehalose and lyophilized indomethacin and trehalose are administered.The horizontal axis of the FIG. 2 indicates tested substances. Thevertical axis of the FIG. 2 indicates ulcer area.

When indomethacin alone (30 mg/kg) was administered ulcer of 4.83±0.90(average of 10 cases±standard deviation) mm² was observed. When mixtureof indomethacin and trehalose (30 mg/kg of indomethacin and 800 mg/kg oftrehalose) was administered ulcer of 4.15±0.86 (average of 5cases±standard deviation) mm² was observed. Thus the rate of suppressedulcer caused by mixed with trehalose was 14.0%. When lyophilizedindomethacin and trehalose (30 mg/kg of indomethacin and 800 mg/kg oftrehalose) was administered ulcer of 2.98±0.54 (average of 10cases±standard deviation) mm² was observed. Thus the rate of suppressedulcer caused by lyophilizing was 38.8%.

FIG. 3 is a graph, which is a substitute of a drawing, which shows a ratulcer index (mm²) when aspirin alone, a mixture of aspirin and trehaloseand lyophilized aspirin and trehalose are administered. The horizontalaxis of the FIG. 3 indicates tested substances. The vertical axis of theFIG. 3 indicates ulcer area. In FIG. 3, the mark * indicates that thereis effective difference.

When aspirin alone (200 mg/kg) was administered ulcer of 10.40±2.73(average of 5 cases±standard deviation) mm² was observed. When mixtureof aspirin and trehalose (200 mg/kg of aspirin and 800 mg/kg oftrehalose) was administered ulcer of 9.25±3.54 (average of 5cases±standard deviation) mm² was observed. Thus the rate of suppressedulcer caused by mixed with trehalose was 11.5%. When lyophilized aspirinand trehalose (200 mg/kg of aspirin and 800 mg/kg of trehalose) wasadministered ulcer of 2.95±1.14 (average of 10 cases±standard deviation)mm² was observed. Thus the rate of suppressed ulcer caused bylyophilizing was 71.6%.

FIG. 4 is a graph, which is a substitute of a drawing, which shows a ratulcer index (mm²) when diclofenac alone, a mixture of diclofenac andtrehalose and lyophilized diclofenac and trehalose are administered. Thehorizontal axis of the FIG. 4 indicates tested substances. The verticalaxis of the FIG. 4 indicates ulcer area. In the FIG. 4, p indicates arejection rate. When diclofenac alone (40 mg/kg) was administered ulcerof 4.30±0.71 (average of 10 cases±standard deviation) mm² was observed.When mixture of diclofenac and trehalose (40 mg/kg of diclofenac and 800mg/kg of trehalose) was administered ulcer of 4.20±1.11 (average of 5cases±standard deviation) mm² was observed. Thus the rate of suppressedulcer caused by mixed with trehalose was 2.3%. When lyophilizeddiclofenac and trehalose (40 mg/kg of diclofenac and 800 mg/kg oftrehalose) was administered ulcer of 1.65±0.43 (average of 10cases±standard deviation) mm² was observed. Thus the rate of suppressedulcer caused by lyophilizing was 61.6%.

The working example 2 shows that lyophilized NSAIDs and trehalose caneffectively suppress ulcer.

Working Example 3 Suppression of Gastric Mucosal Disorder by MolecularInteractions Between Trehalose and NSAIDs 2

Cell viability and cell lethality were measured so as to investigate thesuppression of gastric mucosa disorder caused by molecular interactionsbetween NSAIDs (diclofenac) and trehalose. Powdered diclofenac alone (inFIG. 5, which is described as “Dic”) and lyophilized diclofenac andtrehalose (weight rate diclofenac:trehalose=1:20; if FIG. 5, which isdescribed as “Lyo”) were added and were dissolved separately to DMEMmedia (Sigma) so that the final concentrate in the both of media became2 mM. Then the media were added to 9 to 22 cells of oral epithelialcells Ca. The medium that comprised 1 mM diclofenac or the medium thatcomprised 1 mM diclofenac and 5% trehalose (diclofenac solution andtrehalose solution were added separately to the medium; in FIG. 5, thewhich is described as “Mix”) were added to the 9 to 22 cells of Ca,which are different from those described above. All of the cells wereincubated for 16 hours and cell viability and cell lethality weremeasured by means of LIVE/DEAD Assay (Molecular Probes). We alsoanalyzed for the cells incubated by the usual medium as a control.

In the example, the number of samples, N, were 4 to 6. The result isshown in the FIG. 5.

FIG. 5 is a graph, which is a substitute of a drawing, which shows aneffect for gastric mucosal damages with lyophilized state and mixedstate. FIG. 5A is a graph, which is a substitute of a drawing, whichshows cell viability rate. The vertical axis of the FIG. 5A indicatescell viability [%] and higher value means more cells are alive. FIG. 5Bis a graph, which is a substitute of a drawing, which shows celllethality rate. The vertical axis of the FIG. 5B indicates celllethality [%] and higher value means more cells have been dead. Thushigh cell viability and low cell lethality indicate that cell disorderinduced by diclofenac is suppressed.

FIG. 5 shows that the mixed sample that was merely mixed with solutions(“Mix” in FIG. 5) had the effect of trehalose to suppress cell disorderinduced by the diclofenac. However, lyophilized sample (“Lyo” in FIG. 5)shows more effect of suppressing cell disorder induced by thediclofenac.

Working Example 4 Investigate of Intermolecular Bonding BetweenTrehalose and NSAIDS

DSC, Differential Scanning Calorimetry, was executed to investigate theintermolecular bonding between trehalose and NSAIDs (indomethacin,ibuprofen, aspirin, diclofenac, piroxicam, and Mefenamic acidic). DSCmeasurement was executed for trehalose alone, NSAIDs alone, mixture oftrehalose and NSAIDs, and lyophilized trehalose and NSAIDs. The weightrate between trehalose and NSAIDs is shown in the following table 5.

TABLE 5 NSAIDs:Trehalose Weight rate Indomethacin:Trehalose = 3:80Ibuprofen:Trehalose = 1:2  Aspirin:Trehalose = 1:4  Diclofenac:Trehalose= 1:20 Piroxicam:Trehalose = 3:80 Mefenamic acid:Trehalose = 1:4 

FIGS. 6 to 11 indicates the result of DSC measurement. FIG. 6 is agraph, which is a substitute of a drawing, which shows the result of DSCof torehalose alone, indomethacin alone, a mixture of indomethacin andtrehalose and lyophilized indomethacin. FIG. 7 is a graph, which is asubstitute of a drawing, which shows the result of DSC of torehalosealone, ibuprofen alone, a mixture of ibuprofen and trehalose andlyophilized ibuprofen. FIG. 8 is a graph, which is a substitute of adrawing, which shows the result of DSC of torehalose alone, aspirinalone, a mixture of aspirin and trehalose and lyophilized aspirin. FIG.9 is a graph, which is a substitute of a drawing, which shows the resultof DSC of torehalose alone, diclofenac alone, a mixture of diclofenacand trehalose and lyophilized diclofenac. FIG. 10 is a graph, which is asubstitute of a drawing, which shows the result of DSC of torehalosealone, piroxicam alone, a mixture of piroxicam and trehalose andlyophilized piroxicam. FIG. 11 is a graph, which is a substitute of adrawing, which shows the result of DSC of torehalose alone, Mefenamicacidic alone, a mixture of Mefenamic acidic and trehalose andlyophilized Mefenamic acidic. In the FIGS. 6 to 11, the term “Mixture”means DSC curve for the mixture of trehalose and NSAIDs.

In the FIGS. 6 to 11, the term “lyophilize” means DSC curve for thelyophilized trehalose and NSAIDs. In the FIGS. 6 to 11, the verticalaxis indicates heat flow per mole [W/mol] for trehalose alone or NSAIDsalone. For the mixture and lyophilized compound, the vertical axisindicates heat flow per one mole of trehalose [W/mol] for the mixtureand the lyophilized compound. In the FIGS. 6 to 11, the horizontal axisindicates temperature (degrees C.).

As shown in FIGS. 6 to 11, the peaks of the mixture of NSAIDs andtrehalose are similar to the sum of the peaks of NSAIDs alone and thepeaks of trehalose alone. To the contrary, in the DSC curve oflyophilized compound, the peak which is around 120 degrees C. andderives from trehalose is extinguished or is shifted to low temperaturedirection or high temperature direction.

These facts indicate that lyophilized compound has NSAIDs and trehalosethat have interactive force between them.

The result shown in FIG. 6 indicates that the mixture of indomethacinand trehalose had the first peak at the region of 98 to 102 degrees C.,the second peak at the region of 190 to 210 degrees C. and the thirdpeak at the region of 115 to 125 degrees C. The first peak means thehighest peak (the largest peak of absolute value of DSC measured value)in a DSC curve.

The result of the mixture almost coincides with the peaks of DSC curveof trehalose alone. The DSC curve of the lyophilized indomethacin andtrehalose had the first peak at the region of 80 to 95 degrees C. andthe second peak at the region of 260 to 270 degrees C. The DSC curve ofthe lyophilized indomethacin and trehalose further had the third peak atthe range of 270 to 280 degrees C.

The differences of the positions of peaks between the mixture and thelyophilized compound indicate that the intermolecular compound ofindomethacin and trehalose was generated by lyophilizing the mixedsolution after indomethacin and trehalose were dissolved jointly.

The result shown in FIG. 7 indicates that the mixture of ibuprofen andtrehalose had the first peak at the region of 98 to 102 degrees C., thesecond peak at the region of 70 to 80 degrees C., the third peak at theregion of 190 to 210 degrees C. and the fourth peak at the region of 115to 125 degrees C. The result of the mixture almost coincides with thepeaks of DSC curves of trehalose alone and ibuprofen alone.

The DSC curve of the lyophilized ibuprofen and trehalose had the firstpeak at the region of 98 to 102 degrees C. and the second peak at theregion of 70 to 80 degrees C., the third peak at the range of 175 to 190degrees C. and the fourth peak at the region of 130 to 145 degrees C.Within the DSC peaks of lyophilized ibuprofen and trehalose, the peaksof at the range of 175 to 190 degrees C. and at the region of 130 to 145degrees C. were not found in the DSC curve of the mixture. Thus it showsthat the intermolecular compound of ibuprofen and trehalose wasgenerated by lyophilizing the mixed solution after ibuprofen andtrehalose were dissolved jointly.

The result shown in FIG. 8 indicates that the mixture of aspirin andtrehalose had the first peak at the region of 145 to 150 degrees C. andthe second peak at the region of 98 to 102 degrees C. The DSC curve ofthe lyophilized aspirin and trehalose had the first peak at the regionof 110 to 120 degrees C. and the second peak at the region of 135 to 145degrees C.

The differences of the positions of peaks between the mixture and thelyophilized compound indicate that the intermolecular compound ofaspirin and trehalose was generated by lyophilizing the mixed solutionafter aspirin and trehalose were dissolved jointly.

The result shown in FIG. 9 indicates that the mixture of sodiumdiclofenac and trehalose had the first peak at the region of 95 to 110degrees C. and the second peak at the region of 190 to 220 degrees C.The DSC curve of the lyophilized sodium diclofenac and trehalose had thefirst peak at the region of 90 to 100 degrees C. and the second peak atthe region of 135 to 145 degrees C. The differences of the positions ofpeaks between the mixture and the lyophilized compound indicate that theintermolecular compound of sodium diclofenac and trehalose was generatedby lyophilizing the mixed solution after sodium diclofenac and trehalosewere dissolved jointly.

The result shown in FIG. 10 indicates that the mixture of Mefenamicacidic and trehalose had the first peak at the region of 98 to 102degrees C., the second peak at the region of 225 to 235 degrees C. andthe third peak at the region of 190 to 210 degrees C. The DSC curve ofthe lyophilized Mefenamic acidic and trehalose had the first peak at theregion of 225 to 235 degrees C. and the second peak at the region of 90to 110 degrees C. The absolute values of peak top of the first peak andthe second peak of the lyophilized compound (Absolute value of DSCmeasured value) are larger than the peaks at the regions of 225 to 235and 90 to 110 degrees C. for Mefenamic acidic alone.

The differences of the positions of peaks between the mixture and thelyophilized compound and the difference of SDC result between Mefenamicacidic and trehalose indicate that the intermolecular compound ofMefenamic acidic and trehalose was generated by lyophilizing the mixedsolution after Mefenamic acidic and trehalose were dissolved jointly.

The result shown in FIG. 11 indicates that the mixture of piroxicam andtrehalose had the first peak at the region of 98 to 102 degrees C., thesecond peak at the region of 225 to 235 degrees C. and the third peak atthe region of 190 to 210 degrees C. The DSC curve of the lyophilizedpiroxicam and trehalose had the first peak at the region of 90 to 105degrees C. and the second peak at the region of 195 to 205 degrees C.The absolute values of peak top of the first peak and the second peak ofthe lyophilized compound (Absolute value of DSC measured value) arelarger than the peaks at the regions of 90 to 105 degrees C. and 195 to205 degrees C. The differences of the positions of peaks between themixture and the lyophilized compound and the difference of SDC resultbetween piroxicam and trehalose indicate that the intermolecularcompound of piroxicam and trehalose was generated by lyophilizing themixed solution after piroxicam and trehalose were dissolved jointly.

As shown in FIGS. 6 to 11, the peaks of the mixture of NSAIDs andtrehalose are similar to the sum of the peaks of NSAIDs alone and thepeaks of trehalose alone. To the contrary, in the DSC curve oflyophilized compound, the peak which is around 120 degrees C. andderives from trehalose is extinguished or is shifted to low temperaturedirection or high temperature direction.

These facts indicate that lyophilized compound has NSAIDs and trehalosethat have interactive force between them.

As described the above, the Medical Drugs that comprises trehalose andNSAIDs that have molecular interactions between them, thereby it canalleviate damage of gastrointestinal mucosal induced by NSAIDs, such asdisorder of gastric mucosa induced by NSAIDs. Thus it is shown that theMedical Drugs of the invention reduce damage of gastrointestinal mucosalinduced by NSAIDs.

Working Example 5

Ulcer area was measured by the same conditions in working example 2except for replacing trehalose with maltose, sucrose, or lactose. Weformed lyophilized molecular compound of aspirin with disaccharide(maltose, sucrose, or lactose). The obtained ulcer area is shown in FIG.12. Compared to FIG. 3 and FIG. 12, it is shown that aspirin effectivelysuppress ulcer by forming molecular compound of aspirin withdisaccharide.

Working Example 6

Ulcer area was measured by the same conditions in working example 2except for replacing trehalose with maltose, or lactose. We formedlyophilized molecular compound of diclofenac with disaccharide (maltose,or lactose). The obtained ulcer area is shown in FIG. 13. Compared toFIG. 4 and FIG. 13, it is shown that diclofenac effectively suppressulcer by forming molecular compound of diclofenac with disaccharide.

INDUSTRIAL APPLICABILITY

The present invention may be used in medical industry.

1. A Medical Drugs which reduce damage of gastrointestinal mucosalinduced by non-steroidal anti-inflammatory Drugs, NSAIDs, the MedicalDrugs comprises an intermolecular compound of NSAIDs and a disaccharide;thereby the Medical Drugs has anti-inflammatory effect of the NSAIDs andcan alleviate damage induced by the NSAIDs.
 2. The Medical Drugs inaccordance with claim 1, wherein the NSAIDs is acidic NSAIDs.
 3. TheMedical Drugs in accordance with claim 1, wherein the NSAIDs is one ormore selected from the group of “Aspirin, Sodium salicylate,Salicylamide, Sazapirin, Diflunisal, Ethenzamide, Aluminum aspirin,5-Amino salicylic acidic, Indomethacin, Etodolac, Sodium diclofenac,sulindac, sodium anfenac, proglumetacin maleate, acemetacin, nabumeton,mofezolac, Ibuprofen, Naproxen, Loxoprofen, Flurbiprofen, FlurbiprofenAxetil, Oxaprozin, Tiaprofenic acidic, Pranoprofen, Aluminoprophen,Zaltoprofen, Mefenamic acidic, TolFenamic acidic, Aluminum flufenamate,Ketophenylbutazone, Clofezone, Bucolome, Piroxicam, Lornoxicam,Tenoxicam, Meloxicam, Ampiroxicam, Epirizole, Tiaramide and Elmofazon”4. The Medical Drugs in accordance with claim 1, wherein thedisaccharide is one or more selected from Trehalose, Maltose, Lactoseand Sucrose.
 5. The Medical Drugs in accordance with claim 1, whereinthe form of the Medical Drugs is tablets, granules, or capsules.
 6. TheMedical Drugs in accordance with claim 1, wherein the NSAIDs isIndomethacin, wherein the disaccharide is Trehalose, and wherein a DSCcurve of the intermolecular compound obtained by the method ofdifferential scanning calorimetry, DSC, has a first peak and a secondpeak at 80 to 95 degrees Celsius and 260 to 270 degrees Celsius,respectively.
 7. The Medical Drugs in accordance with claim 1, whereinthe NSAIDs is Ibuprofen, wherein the disaccharide is Trehalose, andwherein a DSC curve of the intermolecular compound obtained by themethod of differential scanning calorimetry, DSC, has a third peak and afourth peak at 175 to 190 degrees Celsius and 130 to 145 degreesCelsius, respectively.
 8. The Medical Drugs in accordance with claim 1,wherein the NSAIDs is Aspirin, wherein the disaccharide is Trehalose,and wherein a DSC curve of the intermolecular compound obtained by themethod of differential scanning calorimetry, DSC, has a first peak and asecond peak at 110 to 120 degrees Celsius and 135 to 145 degreesCelsius, respectively.
 9. The Medical Drugs in accordance with claim 1,wherein the NSAIDs is sodium diclofenac, wherein the disaccharide isTrehalose, and wherein a DSC curve of the intermolecular compoundobtained by the method of differential scanning calorimetry, DSC, has afirst peak and a second peak at 90 to 100 degrees Celsius and 130 to 145degrees Celsius, respectively.
 10. The Medical Drugs in accordance withclaim 1, wherein the NSAIDs is Mefenamic acidic, wherein thedisaccharide is Trehalose, wherein a DSC curve of the intermolecularcompound obtained by the method of differential scanning calorimetry,DSC, has a first peak and a second peak at 225 to 235 degrees Celsiusand 90 to 110 degrees Celsius, respectively, and wherein the absolutevalues of the first peak and the second peak are larger than absolutevalues of a peak at 225 to 235 degrees Celsius and a peak at 90 to 110degrees Celsius in a DSC curve of Mefenamic acidic obtained by themethod of DSC, respectively.
 11. The Medical Drugs in accordance withclaim 1, wherein the NSAIDs is piroxicam, wherein the disaccharide isTrehalose, wherein a DSC curve of the intermolecular compound obtainedby the method of differential scanning calorimetry, DSC, has a firstpeak and a second peak at 90 to 105 degrees Celsius and 195 to 205degrees Celsius, respectively, and wherein the absolute values of thefirst peak and the second peak are smaller than absolute values of apeak at 90 to 105 degrees Celsius and a peak at 195 to 205 degreesCelsius in a DSC curve of piroxicam obtained by the method of DSC,respectively.
 12. The Medical Drugs in accordance with claim 1, whereinthe Medical Drugs is a Medical Drugs of alleviating damage of gastricmucosal.
 13. A method of manufacturing a Medical Drugs of alleviatingdamage of gastrointestinal mucosal induced by non-steroidalanti-inflammatory Drugs, NSAIDs, the Medical Drugs being able to bringanti-inflammatory effect of the NSAIDs and being able to alleviatedamage induced by the NSAIDs, the method comprising steps of: mixing adisaccharide and the NSAIDs so as to obtain a liquid mixture of thedisaccharide and the NSAIDs; and drying the liquid mixture so as toobtain the Medical Drugs.
 14. The method in accordance with claim 13,wherein the NSAIDs is acidic NSAIDs.
 15. The method in accordance withclaim 13, wherein the NSAIDs is one or more selected from the group of“Aspirin, Sodium salicylate, Salicylamide, Sazapirin, Diflunisal,Ethenzamide, Aluminum aspirin, 5-Amino salicylic acidic, Indomethacin,Etodolac, Sodium diclofenac, Sulindac, Sodium Anfenac, ProglumetacinMaleate, Acemetacin, Nabumeton, Mofezolac, Ibuprofen, Naproxen,Loxoprofen, Flurbiprofen, Flurbiprofen Axetil, Oxaprozin, Tiaprofenicacidic, Pranoprofen, Aluminoprophen, Zaltoprofen, Mefenamic acidic,TolFenamic acidic, Aluminum flufenamate, Ketophenylbutazone, Clofezone,Bucolome, Piroxicam, Lornoxicam, Tenoxicam, Meloxicam, Ampiroxicam,Epirizole, Tiaramide and Elmofazon”
 16. The method in accordance withclaim 13, wherein the disaccharide is one or more selected fromtrehalose, maltose, lactose and sucrose.